Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

• Published in: British journal of cancer Vol. 95; no. 9; pp. 1220 - 1228
• Main Authors: BYRON, S. A, HORWITZ, K. B, RICHER, J. K, LANGE, C. A, ZHANG, X, YEE, D
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 06.11.2006
• Subjects: Antibodies, Monoclonal - pharmacology; Biological and medical sciences; Biology; Biomarkers; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Breast Neoplasms - physiopathology; Cancer research; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Clinical trials; Gene Expression - drug effects; Gynecology. Andrology. Obstetrics; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor I - pharmacology; Insulin-like growth factors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - physiology; Mammary gland diseases; Medical research; Medical sciences; Metastasis; Motility; Phosphoproteins - genetics; Phosphoproteins - physiology; Proteins; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - immunology; Receptor, IGF Type 1 - physiology; RNA Interference; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - physiology; Transfection; Translational Therapeutics; Tumors; Minneapolis Minnesota; United States > US; Cell proliferation; type I insulin-like growth factor receptor insulin receptor substrate; proliferation; Breast cancer; Malignant tumor; Insulin like growth factor 1; type I insulin-like growth factor receptor; Substrate; Mammary gland diseases; insulin-like growth factor-I; Insulin like growth factor; Cancerology; motility; Insulin receptor; Tumor cell; Biological receptor; Hormonal receptor
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6603354

Activation of the type I insulin-like growth factor receptor (IGF-IR) regulates several aspects of the malignant phenotype, including cancer cell proliferation and metastasis. Phosphorylation of adaptor proteins downstream of IGF-IR may couple IGF action to specific cancer phenotypes. In this study, we sought to determine if insulin receptor substrate-1 and -2 (IRS-1 and -2) mediate distinct biological effects in breast cancer cells. Insulin receptor substrate-1 and IRS-2 were expressed in T47D-YA breast cancer cells, which lack IRS-1 and -2 expression, yet retain functional IGF-IR. In the absence of IRS-1 and -2 expression, IGF-IR activation was unable to stimulate proliferation or motility in T47D-YA cells. Expression of IRS-1 resulted in IGF-I-stimulated proliferation, but did not affect motility. In contrast, expression of IRS-2 enhanced IGF-I-stimulated motility, but did not stimulate proliferation. The alphaIR-3, an inhibitor of the IGF-IR, was unable to affect these IGF-stimulated phenotypes unless IRS-1 or -2 was expressed. Thus, IGF-IR alone is unable to regulate important breast cancer cell phenotypes. In these cells, IRS proteins are required for and mediate distinct aspects of IGF-IR-stimulated behaviour. As multiple agents targeting the IGF-IR are currently in early clinical trials, IRS expression should be considered as a potential biomarker for IGF-IR responsiveness.